Ring-substituted amphetamines, such as +/-3,4 methylenedioxymethamphetamine and fenfluramine are well documented serotonin neurotoxins in every animal species tested to date, including non-human primates. Both of these compounds are also used by humans. The present project is designed to determine whether MDMA and fenfluramine are also neurotoxic in humans, and if so, the clinical consequences of such damage. In initial studies, human MDMA users were found to have selective decreases in CSF concentrations of 5-HIAA, the principal serotonin metabolite. These individuals were also found to have alterations in impulsivity and aggression, as well as sleep architecture, three behavioral functions thought to be modulated by serotonin. Ongoing studies are aimed at confirming and extending initial findings. Preliminary data indicate that MDMA-exposed individuals have altered behavioral responses to m-CPP, a serotonin agonist. Personality measures indicate increased impulsivity in MDMA users compared with controls (who also have a history of drug use, but no exposure to MDMA). Results from neuronendocrine studies, pain testing, CSF analysis of monoamine metabo- lites, and PET studies with (11C)MCN5652, a neuroligand selective for the serotonin transporter, are pending.